Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production.
Inhibitors of Mycobacterium tuberculosis EgtD target both substrate binding sites to limit hercynine production.
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DOI：
10.1038/s41598-021-01526-6
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发表时间：
2021-11-15
影响因子：
4.6
通讯作者：
Ronning DR
中科院分区：
文献类型：
--
作者：
Sudasinghe TD;Banco MT;Ronning DR
麦角硫因（EGT）是一种低分子量组氨酸甜菜碱，在所有生命领域都是必需的，但仅由少数生物合成。利用结核分枝杆菌（M. tuberculosis）合成EGT。结核病）对于维持生物能量稳态和保护细菌免受烷基化剂、氧化应激和抗结核药物的影响至关重要。EgtD是一种S-腺苷甲硫氨酸依赖性甲基转移酶（S-adenosylmethionine-dependent methyltransferase，EGT-Met），催化L-组氨酸的三甲基化，启动EGT的生物合成。TB.在这项工作中，文库筛选和结构指导的策略确定了多个类别的M。tb EgtD抑制剂结合在酶活性位点的各个区域。EgtD-抑制剂复合物的X-射线晶体结构证实，L-组氨酸类似物仅结合于L-组氨酸结合位点，而药物样抑制剂如TGX-221和S-Glycyl-H-1152跨越L-组氨酸和甘氨酸Met结合位点。这些酶抑制剂复合物提供了化合物支架的详细结构信息，可用于开发更有效的抑制剂，通过削弱重要的细菌防御来缩短结核病治疗方案。
Ergothioneine (EGT) is a low molecular weight histidine betaine essential in all domains of life but only synthesized by selected few organisms. Synthesis of EGT by Mycobacterium tuberculosis (M. tb) is critical for maintaining bioenergetic homeostasis and protecting the bacterium from alkylating agents, oxidative stress, and anti-tubercular drugs. EgtD, an S-adenosylmethionine-dependent methyltransferase (AdoMet), catalyzes the trimethylation of L-Histidine to initiate EGT biosynthesis and this reaction has been shown to be essential for EGT production in mycobacteria and for long-term infection of murine macrophages by M. tb. In this work, library screening and structure-guided strategies identified multiple classes of M. tb EgtD inhibitors that bind in various regions of the enzyme active site. X-ray crystal structures of EgtD-inhibitor complexes confirm that L-Histidine analogs bind solely to the L-Histidine binding site while drug-like inhibitors, such as TGX-221, and S-Glycyl-H-1152 span both the L-Histidine and AdoMet binding sites. These enzyme-inhibitor complexes provide detailed structural information of compound scaffolds useful for developing more potent inhibitors that could shorten Tuberculosis treatment regimens by weakening important bacterial defenses.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
7.4
作者：
Banco, Michael T.;Mishra, Vidhi;Ronning, Donald R.
通讯作者：
Ronning, Donald R.
影响因子：
30.3
作者：
Napier RJ;Rafi W;Cheruvu M;Powell KR;Zaunbrecher MA;Bornmann W;Salgame P;Shinnick TM;Kalman D
通讯作者：
Kalman D
DOI：
10.4049/jimmunol.1201538
发表时间：
2012-10-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bruns H;Stegelmann F;Fabri M;Döhner K;van Zandbergen G;Wagner M;Skinner M;Modlin RL;Stenger S
通讯作者：
Stenger S
影响因子：
4.4
作者：
Kurz, Sebastian G.;Furin, Jennifer J.;Bark, Charles M.
通讯作者：
Bark, Charles M.